Meningioma Subgroups Associated with Functional Genomic Elements Defined by DNA Methylation
Malta TM, Snyder J, Wells M, De Carvalho A, Poisson L, Souza C, Zadeh G, Aldape K, Tirapelli D, Carlotti C, Lee Y, Kalkanis S, Walbert T, and Noushmehr H. Meningioma Subgroups Associated with Functional Genomic Elements Defined by DNA Methylation. Cancer Res 2019; 79(13).
Although most meningioma are non-malignant, there is a high recurrence rate among atypical and anaplastic (malignant) meningiomas (grades II/III). In addition, malignant meningioma usually progresses after treatment. Recently, based on DNA methylation, two subgroups of meningioma were described with recurrence-free survival differences. Epigenetic deregulation at distinct genomic elements can affect changes in gene expression and alter the transcriptional profile of the cancer cells. We seek to understand the mechanisms of meningioma recurrence and progression after initial treatment. In order to address this, we will use DNA methylation data to identify candidate noncoding elements and their connection with genes that might explain differences in meningioma prognostic subgroups. Using published DNA methylation data we compared favorable and unfavorable meningioma subgroups and identified 3, 045 differentially methylated probes (p< 0.0001, difference mean-methylation beta-value> 0.2). Focusing on probes within known functional genomics, we identified 18 highly conserved genomic enhancers known to be activated in cancer that can potentially drive meningioma recurrence. We next investigated links between these enhancers and their targeted genes by incorporating GeneHancer annotation. We found that the unfavorable subgroup of meningiomas presented hypomethylation within enhancer regions that have the potential to target PARK7, ARID4B, and FBH1. ARID4B was previously shown to be highly active in high-grade meningiomas. We also identified 16 enhancer regions that overlap known prognostic cancer enhancer, previously identified in other tumor types. Our findings were validated in independent cohort comprised by public and unpublished DNA methylation datasets. Our preliminary results are the first to suggest that DNA methylation changes can be used to identify noncoding regions associated with meningioma prognosis. Identification of noncoding regions associated with meningioma recurrence will provide knowledge of the role of epigenomics in the development of malignant meningioma and of opportunities for targeted therapy.